Radioiodine (131I) targets thyroid tissues and has been an effective and standard treatment for differentiated thyroid cancers for many years. However, the Na +/| symporter (NIS), which mediates active iodide uptake into thyroid follicular cells, is also abundantly expressed in salivary ductal cells. Accordingly, many 131I-treated thyroid cancer survivors suffer from life-long morbidity of 131I-induced salivary gland (SG) dysfunction, including recurrent sialadenitis, persistent xerostomia, and progressive susceptibility to dental caries and periodontal disease. In this proposal, we aim to explore novel approaches to prevent 131I-induced SG damage in thyroid cancer patients, and to identify protective saliva biomarkers for patients' susceptibility to progressive 131I-induced SG dysfunction. Two specific aims are identified: (1) Transient silencing/inhibition of salivary NIS to eliminate salivary 131I accumulation during radioiodine therapy; and (2) Identify protective saliva biomarkers and underlying pathobiology for 131I-induced SG dysfunction. Upon successful completion of the proposed studies, our novel prevention strategy promises to eliminate 131I-induced SG damage or at least dramatically reduce its occurrence among thyroid cancer survivors who will receive 131I therapy. We will be able to use quantifiable saliva biomarkers or SG anatomic changes to monitor the onset and progression of SG dysfunction induced by 131I such that personalized intervention strategies can be applied to patients in a timely manner. We will determine whether saliva biomarkers detected in the early stage of salivary dysfunction induced by 131I are predictive of future progression to chronic disease. We may also distinguish patients who are more susceptible or resistant to develop life-long morbidity of 131I-induced SG dysfunction for differential clinical management.